Many immunologic, infectious, and biochemical agents are associated with the etiology of inflammatory arthritis. The final common pathology, however, involves diapedesis of leukocytes out of the bloodstream and into the soft tissues of the joint. My laboratory has found that the cell adhesion molecule PECAM-1 (CD31) on leukocytes and endothelial cells plays an important role in this process. Blocking either leukocyte PECAM or endothelial cell PECAM blocks diapedesis in models of inflammation in vitro and in vivo. Anti-inflammatory therapy targeting cell adhesion molecules have been successful in many animal models of disease; however, there have been relatively few studies in arthritis models. We have produced transgenic mice expressing soluble recombinant murine PECAM as a chimeric IgG fusion protein. Despite therapeutic serum levels of mPECAM-IgG, these mice are healthy and appear normal until given an inflammatory challenge. These mice are then resistant to acute inflammation. We will develop models of inflammatory arthritis in mice and test the role of PECAM in the development of the inflammation. The circulating decoy PECAM should prevent leukocyte PECAM-endothelial PECAM interaction and thus reduce or prevent arthritis. Many anti-inflammatory agents can prevent arthritis when given before induction of the disease. However, in this case it is not clear whether the effect of the therapy is to block induction of arthritis or to prevent the inflammatory sequelae. On the other hand, it is relatively difficult to treat ongoing arthritis once the disease is established. Yet, this is the situation that clinicians face in treating arthritic patients. We have also produced transgenic mice in which the PECAM-IgG chimeric protein is controlled by an inducible promoter. The most important aim of this proposal will employ these mice to study the efficacy of PECAM-IgG in blocking the progression of established disease. Arthritis will be induced in these mice, then littermates matched for sex, size and severity of arthritis will be randomized to treatment groups. In some groups the PECAM-IgG will be induced (Therapeutic levels of mPECAM-IgG are found in the circulation within 8 hours.) and its effect on the progression of the pre-existing arthritis will be monitored clinically and histopathologically.